Hyperhomocysteinemia (HHcy) has been recognized as a potent risk factor for cardiovascular disease (CVD). Several biological mechanisms have been suggested to explain cardiovascular pathological changes associated with HHcy. It has been reported that HHcy accelerates atherosclerosis by inhibiting endothelial cell (EC) growth, post-injury re-endothelialization, endothelial-dependent vessel relaxation and HDL biosynthesis (Zhang, D et al., Circulation research, 2012; 111:37-49; Tan, H et al., Cardiovascular research, 2006; 69:253-262; Jamaluddin, M D et al., Blood, 2007; 110:3648-3655; Jiang, X et al., Arteriosclerosis, thrombosis, and vascular biology, 2005; 25:2515-2521; Wang, H et al., Blood, 2003; 101:3901-3907; Liao, D et al., Circulation research, 2006; 99:598-606; and Cheng, Z et al., Blood, 118:1998-2006). It has also been reported that HHcy impairs re-endothelialization and promotes post-injury neointimal formation via inhibiting EC proliferation and migration (Tan, H et al., Cardiovascular research, 2006; 69:253-262).
It is known that bone marrow (BM)-derived endothelial progenitor cells (EPCs) can enter the circulation, home to the injured endothelium and ischemic myocardium, and participate in re-endothelialization (Kawamoto, A et al., Circulation, 2003; 107:461-468 and Chen, J Z et al., Journal of molecular and cellular cardiology, 2004; 36:233-239). Circulating EPC population can be identified as CD34+ alone, CD34+/VEGFR2+, or CD34+/CD31+, which is decreased in patients with atherosclerosis, stroke, and hemodialysis (Werner, N et al., N Engl J Med., 2005; 353:999-1007; Mano, R et al., Atherosclerosis, 2009; 204:544-548; Jourde-Chiche, N et al., J Thromb Haemost, 2009; 7:1576-1584; and Alam, M M et al., J Cereb Blood Flow Metab, 2009; 29:157-165). The Framingham study (Werner, N et al., N Engl J Med., 2005; 353:999-1007) showed that circulating EPCs is associated with cardiovascular risk scores, a clinical index for 10-year risk of developing coronary heart disease (CHD) based on age, total cholesterol level, HDL cholesterol level, smoke and systolic blood pressure. Decreased EPC population is associated with carotid intima-media thickness and flow-mediated vascular dilation in hypertensive patients (Bogdanski, P et al., Clinical chemistry and laboratory medicine: CCLM/FESCC, 2012; 50:1107-1113 and Delva, P et al., Journal of hypertension, 2007; 25:127-132) and associated with endothelial dysfunction in dialysis patients with chronic kidney disease (CKD) (Jourde-Chiche, N et al., J Thromb Haemost, 2009; 7:1576-1584 and Jourde-Chiche, N et al., Seminars in dialysis, 2011; 24:327-337). It was reported that elevated plasma levels of Hcy reduced circulating EPC counts in patients with CHD (Huang, C et al., Acta cardiologica, 2011; 66:773-777). However, the effect of HHcy on EPC generation and its impact on vascular injury has not been studied. The mechanism underlying HHcy-impaired EPC function is unknown.
Since EPCs were first described more than a decade ago, many groups focused especially on its regenerative potential and tried to unravel their unique properties and characteristics with the ultimate goal to improve the clinical applicability and efficacy of these cells in the fight against CVD. Although extensive work has been conducted to verify if EPC impairment plays a key role in coronary atherogenesis (Kawamoto, A et al., Circulation, 2003; 107:461-468), it remains unclear if these cells exert favorable or unfavorable effects at sites of percutaneous coronary intervention (PCI) due to discordant definitions of EPCs and different timing of EPC sampling (Kawamoto, A et al., Circulation, 2003; 107:461-468; Chen, J Z et al., Journal of molecular and cellular cardiology, 2004; 36:233-239; and Werner, N et al., N Engl J Med., 2005; 353:999-1007). In addition, development of de novo lesions and post-PCI restenosis are patho-physiologically dissimilar. The role of EPCs in restenosis progression needs to be examined concomitantly and serially over time.
There is a need in the art for vascular repair therapies in subjects with metabolic disorders. The present invention addresses this unmet need.